3-[(1R,2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl]phenol is the IUPAC name for Tapentadol (Formula I). It is a centrally acting analgesic with a dual mode of action as an agonist of μ-opioid receptor and as a norepinephrine reuptake inhibitor.
U.S. Pat. No. 6,248,737 reissued as U.S. RE39593 discloses a variety of 1-phenyl-3-dimethylaminopropane compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and methods of use thereof. Among them, Tapentadol hydrochloride, is a one compound which has analgesic activity.
As per the process exemplified in U.S. RE39593 (hereinafter referred to as the '593 patent), (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is prepared by the reaction of (-)-(2S,3 S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with thionyl chloride to produce (-)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride; followed by subsequent removal of the chlorine substituent by treatment with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride, to produce (-)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride; which is then converted into (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol hydrochloride by reaction with concentrated hydrobromic acid at reflux. Separation of the diastereoisomers, that is the two enantiomeric pairs, is carried out by precipitation of hydrochloride with trimethylchlorosilane/water in 2-butanone. The resolution of the racemic mixture of the two enantiomers of (2R,3R) and (2S,3S) configuration is carried by separation on a chiral HPLC column.
WO02004/108658 describes process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine, the penultimate intermediate to prepare tapentadol, wherein the compound (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, is heated in acidic medium to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethylamine HCl, which on catalytic hydrogenation yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3 S))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine. The required stereoisomer is separated to get (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine, which is treated with concentrated hydrobromic acid to get tapentadol.
WO2005/000788 describes another method of preparing tapentadol, wherein compound (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol is subjected to dehydration reaction using heterogeneous catalyst to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethyl amine hydrochloride, which on catalytic reduction yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3 S))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine. The required stereoisomer is separated to get (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine.
WO2008/012046 describes another method for the preparation of tapentadol, wherein 1-(3-(benzyloxy)phenyl)propan-1-one is reacted with N-Methyl-N-methylene-methaneaminium chloride in presence of acetyl chloride and solvent acetonitrile to obtain compound 1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The compound is resolved with L-(-)-dibenzoyltartaric acid to get (S)-1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The isolated compound is then reacted with ethyl magnesium bromide undergoing Grignard reaction to isolate (2S,3R)-3-(3-(benzyloxy)phenyl)-1-(dimethylamino)-2-methylpentan-3-ol, which on reaction with trifluoroacetic anhydride in acetic acid results in acetylated compound. The acetylated compound on hydrogenolysis results in the compound 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol of Formula-I.
WO2008012047 discloses a method for the preparation of tapentadol, wherein 1-(3-methoxyphenyl)propan-1-one is used as starting which converted to a hydroxyl intermediate compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol through sequential reactions. Then this compound dehydrated to yield the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, which after hydrogenation gives the mixture of compound (2R,3R))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methane sulphonic acid and treated with methionine to get the compound 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, which is isolated as hydrochloride salt of tapentadol hydrochloride.
US20130137890 discloses preparation of tapentadol through the reaction of (S)-1-(dimethylamino)-2-methylpentan-3-one with 3-bromoanisole under Grignard conditions to get the compound (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol which convert into sulfonate esters followed by reductive deoxygenation to yield (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and demethylation to obtain the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol (tapentadol).
US20130096346 also discloses a preparation method of tapentadol through reacting an enantiomeric pair (2R,3R)/(2S,3 S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol or an acid addition salt thereof with trifluoroacetic anhydride in a first solvent to produce a reaction mass, hydrogenating the reaction mass to produce an enantiomeric pair (2R,3R)/(2S,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine or an acid addition salt thereof, resolving the enantiomeric pair with a suitable optically active acid to produce an enantiomerically pure (-)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine, demethylating the enantiomerically pure compound using a demethylating agent in a second solvent to produce tapentadol.
In spite of so many known processes, there is still need to have an efficient, economic and a safe process. The present inventors have found a novel process for preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, tapentadol of Formula I.